Expansion of CAG/CTG repeats in DNA is the underlying cause of >14 genetic disorders, including Huntington disease (HD) and myotonic dystrophy. The mutational process is ongoing, with increases in repeat size enhancing the toxicity of the expansion in specific tissues. In many repeat diseases, the repeats exhibit high instability in the striatum, whereas instability is minimal in the cerebellum. In recent work using specific DNA repair assays, we have provided molecular insights into how the tissue-selective instability of CAG/CTG repeats may arise. In particular, our results show that the BER protein stoichiometry, overall nucleotide sequence, and DNA damage position can modulate repair outcome and that a suboptimal long-patch BER activity promotes CAG/CTG repeat instability. Moreover, we have found that the BER DNA glycosylase NEIL1 contributes to germline and somatic CAG repeat expansion in HD and that the binding and strand incision efficiency of the major human abasic endonuclease, APE1, is influenced by domain sequence, conformation, AP site location/relative positioning and duplex thermodynamic stability. Our results have both predictive and mechanistic implications for the success and failure of repair protein activity at such oxidatively sensitive, conformationally plastic/dynamic repetitive DNA domains. Single-strand break repair (SSBR) is an important subpathway of BER. Recent data has found a genetic linkage between proteins of SSBR aprataxin, tyrosyl-DNA phosphodiesterase 1 and DNA polynucleotide kinase phosphatase and human neurological disorders, implicating this repair mechanism in protection against neuronal cell loss and brain function. Ataxia with oculomotor apraxia 1 (AOA1) is caused by mutation in the APTX gene, which encodes the stand break repair protein aprataxin. Aprataxin removes 5-adenylate groups in DNA that arise from aborted ligation reactions. AOA1 is characterized by global cerebellar atrophy, highlighted by loss of Purkinje cells, ocular motor apraxia, and motor and sensory neuropathy. Strikingly, AOA1 patients lack the cancer susceptibility and other peripheral symptoms (e.g., immunological deficiencies) commonly associated with other inherited disorders stemming from a DNA repair defect. We have reported that aprataxin activity is necessary for maintaining optimal mitochondrial function, indicating that there is likely a mitochondrial component to the disease phenotype of AOA1. In a separate study, we have found that deficiency in a key SSBR/BER protein, i.e., XRCC1, is a risk factor for cellular damage caused by ischemic brain injury and impairs recovery following stroke induction. Additional studies have revealed that a modest decrement in SSBR/BER capacity, via polymerase &#946; haploinsufficiency, can render the brain more vulnerable to Alzheimer Disease (AD)-related molecular and cellular alterations. Lastly, our data indicate that because of their higher BER capacity, proliferative neural progenitor cells are more efficient at repairing DNA damage compared with their neuronally differentiated progeny, perhaps increasing the vulnerability of neurons to oxidative stress. Cockayne Syndrome (CS) is an autosomal recessive disorder, characterized by growth failure, neurological abnormalities, premature aging symptoms, and cutaneous photosensitivity, but no increased cancer incidence. CS is divided into two strict complementation groups: CSA (mutation in CKN1) and CSB (mutation in ERCC6). Of the patients suffering from CS, 80% have mutations in the CSB gene. Our past work has helped define the biochemical properties of CSB, revealing that the protein interacts with a diverse range of nucleic acid substrates and likely has important ATP-dependent and ATP-independent functions. More recent results, obtained in collaboration with Dr. Vilhelm Bohr, suggest that CSB plays a role in both nuclear and mitochondrial BER, and may act as a mitochondrial DNA damage sensor, inducing mitochondrial autophagy in response to stress. In light of a few recent observations, we are currently pursuing the two component hypothesis that (i) defects in nucleolar operations give rise to the profound developmental defects of the disease, while (ii) defects in the repair of transcription-blocking lesions contribute to the post-developmental tissue decline and mitochondrial dysfunction. In particular, our recent work indicates that CSB coordinates the resolution of ICLs, possibly in a transcription-associated repair mechanism involving the 5 to 3 exonuclease SNM1A, implying that defects in the process could contribute to the post-mitotic degenerative pathologies associated with CS.